CN115531289A - Lacrimal duct suppository for slowly releasing tafluprost and preparation method thereof - Google Patents

Lacrimal duct suppository for slowly releasing tafluprost and preparation method thereof Download PDF

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CN115531289A
CN115531289A CN202211342754.6A CN202211342754A CN115531289A CN 115531289 A CN115531289 A CN 115531289A CN 202211342754 A CN202211342754 A CN 202211342754A CN 115531289 A CN115531289 A CN 115531289A
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tafluprost
plug
chitosan
slowly releasing
preparing
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宋爽
喻晓兵
王磊
师自安
张鹏
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Beijing Hospital
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts, ocular implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

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Abstract

The invention discloses a preparation method of a lacrimal duct suppository for slowly releasing tafluprost, which comprises the following steps: (1) Dispersing tafluprost, polytrimethylene carbonate, chitosan and trilysine in a solvent and uniformly mixing, wherein the mass ratio of the tafluprost to the polytrimethylene carbonate to the chitosan to the trilysine is 0.001-0.5: 15-35: 10-35: 0.5-2; (2) Performing crosslinking reaction at 40-50 deg.C for 8-20 hr, cooling, and drying to obtain mixture; (3) And (3) carrying out plasma treatment on the mixture obtained in the step (2) for 30s-5min under the condition of less than 6pa, and then curing and forming to obtain the canaliculus plug for slowly releasing tafluprost. The method takes the tafluprost, the polytrimethylene carbonate, the chitosan and the trilysine as raw materials to carry out cross-linking reaction, and then the plasma treatment is adopted to prepare the lacrimal canaliculus suppository for slowly releasing the tafluprost, which can reduce the times of using antibiotic medicines or does not need to use the antibiotic medicines, has good patient compliance, good comfort level, good biocompatibility, short-term degradation, small side effect, good water swelling performance, difficult shedding, intraocular pressure reduction while treating xerophthalmia and low corneal toxicity.

Description

Lacrimal duct suppository for slowly releasing tafluprost and preparation method thereof
Technical Field
The invention relates to the field of medical materials, in particular to a lacrimal duct suppository for slowly releasing tafluprost and a preparation method thereof.
Background
Dry eye refers to a general term for a variety of diseases characterized by abnormal quality or quantity or abnormal kinetics of tear fluid from any cause, resulting in decreased tear film stability, and accompanying ocular discomfort and ocular surface tissue pathology. Common symptoms include dry eyes, easy tiredness, itching eyes, foreign body sensation, burning sensation, viscous secretion, aversion to wind, photophobia and sensitivity to external stimulation. It has been found that a significant proportion of patients suffer from dry eye with glaucoma, dry eye with ocular hypertension.
In recent years, treatment is increasingly performed clinically by using a punctum plug or a lacrimal passage plug, and the punctum plug or the lacrimal passage plug reduces the discharge of tears, reestablishes the balance of ocular surface tears and improves the ocular surface environment by blocking the lacrimal passage, thereby relieving the symptoms and signs of xerophthalmia. However, in the case of patients with dry eye complicated with glaucoma and dry eye complicated with ocular hypertension, it is necessary to administer antibiotic drugs several times, and there is a need to develop a punctum plug capable of effectively treating dry eye complicated with glaucoma and dry eye complicated with ocular hypertension.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide the lacrimal duct suppository for slowly releasing the tafluprost and the preparation method thereof, the prepared lacrimal duct suppository for slowly releasing the tafluprost can reduce the times of using antibiotic medicines or does not need to use the antibiotic medicines, has good patient compliance, good comfort level, good biocompatibility, short-term degradation, small side effect, good water swelling performance and low corneal toxicity, is not easy to fall off, can treat xerophthalmia and simultaneously reduce intraocular pressure, and can treat xerophthalmia.
In order to achieve the purpose of the invention, the invention provides the following technical scheme:
in a first aspect, the present invention provides a method for preparing a punctum plug for the sustained release of tafluprost, comprising the steps of:
(1) Dispersing tafluprost, polytrimethylene carbonate, chitosan and trilysine in a solvent, and uniformly mixing, wherein the mass ratio of the tafluprost to the polytrimethylene carbonate to the chitosan to the trilysine is 0.001-0.5: 15-35: 10-35: 0.5-2;
(2) Performing crosslinking reaction at 40-50 deg.C for 8-20 hr, cooling, and drying to obtain mixture;
(3) And (3) carrying out plasma treatment on the mixture obtained in the step (2) for 30s-5min under the condition of less than 6pa, and then curing and forming to obtain the canaliculus plug for slowly releasing tafluprost.
Preferably, in step (1), the mass ratio of tafluprost to polytrimethylene carbonate to chitosan to trilysine is 0.001-0.02: 25-35: 20-35: 0.5-1.
Preferably, in step (1), the solvent is acetic acid.
Preferably, in step (2), the crosslinking reaction is carried out at 45 to 50 ℃.
Preferably, in step (2), the crosslinking reaction is carried out for 12 to 20 hours.
Preferably, in step (3), the plasma treatment conditions include a treatment pressure of 3 to 5Pa, a treatment time of 30s to 3min, a flow rate of Ar of 1 to 3L/min, and a power of 50 to 90W.
Preferably, in step (3), when cured into a cylindrical shape, the diameter is 0.1 to 1mm and the length is 0.5 to 10mm.
Preferably, in step (3), when cured into a cylindrical shape, the diameter is 0.1 to 0.5mm and the length is 0.5 to 3mm.
Preferably, in step (3), when the cured and formed cylinder shape, at least one row of tear holes is opened along the central axis direction, and the diameter of the row of tear holes is 0.02mm-0.2mm.
In a second aspect, the present invention provides a punctum plug that sustains the release of tafluprost, which is prepared according to the above preparation method.
The invention has the beneficial effects that:
the tafluprost, the polytrimethylene carbonate, the chitosan and the trilysine are used as raw materials to carry out cross-linking reaction, and the lacrimal canaliculus suppository for slowly releasing the tafluprost, which is prepared by adopting plasma treatment, can reduce the times of using antibiotic medicines or does not need to use the antibiotic medicines, has good patient compliance, good comfort level, good biocompatibility, short-term degradation and small side effect, reduces intraocular pressure while treating xerophthalmia and has low corneal toxicity; the inventor finds that the lacrimal duct suppository capable of slowly releasing the tafluprost can obtain very good hydrophilicity and water swelling property through plasma treatment, can quickly swell in water, can quickly swell in the lacrimal duct within a few seconds after being implanted, and is further fixed in the lacrimal duct and not easy to fall off.
The prepared lacrimal duct suppository for slowly releasing the tafluprost has important clinical application value. It should be noted that the lacrimal canaliculus suppository for slowly releasing tafluprost prepared by the invention can effectively treat xerophthalmia combined glaucoma and xerophthalmia combined ocular hypertension, but the xerophthalmia combined glaucoma or xerophthalmia combined ocular hypertension mentioned by the invention is only a disease which is usually treated by applying the lacrimal canaliculus suppository for slowly releasing tafluprost prepared by the invention, the invention is not limited to be applied to the ocular diseases, and the lacrimal canaliculus suppository for slowly releasing tafluprost can be applied to any other suitable ocular diseases.
The features and advantages of the present invention will be described in detail in the detailed description that follows.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to specific embodiments. It should be understood that the specific examples described in the following description of the embodiments of the present invention are merely illustrative of specific embodiments of the present invention and are intended to be used for the purpose of explanation, not limitation, of the invention.
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and these ranges or values should be understood to encompass values close to these ranges or values, which refer to values such as ± 10% of the specified point value. For numerical ranges, each range between its endpoints and individual point values, and each individual point value can be combined with each other to give one or more new numerical ranges, and such numerical ranges should be construed as specifically disclosed herein. In the description of the present application, the word "plurality" and the like mean two or more unless otherwise specified. Furthermore, the terms "comprises," "comprising," and any variations thereof, are intended to cover non-exclusive inclusions.
In a first aspect, the present invention provides a method for preparing a punctum plug for sustained release of tafluprost, comprising the steps of:
(1) Dispersing tafluprost, polytrimethylene carbonate, chitosan and trilysine in a solvent, and uniformly mixing, wherein the mass ratio of the tafluprost to the polytrimethylene carbonate to the chitosan to the trilysine is 0.001-0.5: 15-35: 10-35: 0.5-2;
(2) Performing crosslinking reaction at 40-50 deg.C for 8-20 hr, cooling, and drying to obtain mixture;
(3) And (3) carrying out plasma treatment on the mixture obtained in the step (2) for 30s-5min under the condition of less than 6pa, and then curing and forming to obtain the canaliculus plug for slowly releasing tafluprost.
In the present invention, tafluprost is to be understood in a broad sense and also includes analogs or derivatives thereof. Tafluprost mainly acts to lower intraocular pressure.
At present, the tafluprost eye drops are mainly used for treatment, but researches show that the tafluprost eye drops contain preservatives to different degrees, which become the main cause of corneal toxicity of patients after long-term use (generally more than 1 year), the eye drops are characterized by superficial punctate corneal epithelial lesions, are weighted under the nose, and punctate staining can be diffuse or flaky along with the prolonging of the administration time and the strengthening of the toxicity degree; besides, the tafluprost can cause corneal toxicity to a certain extent, and the lacrimal canaliculus suppository of the invention has no preservative component, so that the corneal toxicity can be reduced to a large extent, and the corneal toxicity is low.
In the present invention, the molecular weight of the polytrimethylene carbonate can be selected within a wide range. Preferably, in order to further reduce the times of using the antibiotic medicines or avoid using the antibiotic medicines, the lacrimal duct suppository for slowly releasing the tafluprost has the advantages of good patient compliance, good comfort, good biocompatibility, small side effect, short-term degradation, good water swelling performance and difficult shedding, and the weight average molecular weight of the polytrimethylene carbonate is 10000-100000.
In the present invention, the kind of chitosan may be selected from a wide range, such as carboxymethyl chitosan. The molecular weight of chitosan can also be selected within a wide range. Preferably, in order to further reduce the times of using antibiotic medicines or avoid using antibiotic medicines, the lacrimal duct suppository for slowly releasing the tafluprost has the advantages of good patient compliance, good comfort, good biocompatibility, small side effect, short-term degradation, good water swelling performance and difficult shedding, and the weight-average molecular weight of the chitosan is 50000-150000.
It should be noted that although the lacrimal canaliculus is part of the lacrimal passage structure in the strict medical professional sense, since the medical professional meanings of "lacrimal canaliculus" and "lacrimal passage" are not necessarily strictly regulated in practical use, the "punctum plug" in the present invention is to be understood in a broad sense, that is, the "punctum plug" is equivalent to the "lacrimal passage", and thus the "punctum plug" in the present invention is equivalent to the "lacrimal passage plug".
The mechanical strength of the lacrimal duct suppository is small, the lacrimal duct suppository is easy to fall off, the mechanical strength is high, foreign body sensation is easy to occur, the lacrimal duct suppository is not comfortable enough, the curative effect is not good for exertion, and adverse reaction is easy to generate. In the invention, the polytrimethylene carbonate and chitosan and other raw materials are adopted to be matched together, so that the lacrimal duct plug has proper mechanical strength and good comfort; the lacrimal canaliculus suppository also has good biocompatibility, water swelling property and small side effect; and the polytrimethylene carbonate and the chitosan are taken as main raw materials, so that the slow release of tafluprost can be well crosslinked and promoted, the release speed is more stable, the therapeutic effect can be favorably exerted, and the anti-inflammatory effect is realized.
In the present invention, the kind of the solvent may be selected from a wide range as long as it can dissolve tafluprost, polytrimethylene carbonate, chitosan and trilysine. Preferably, the solvent is acetic acid (as broadly understood, such as an aqueous solution of acetic acid at a molar concentration of 3% to 10%) in order to make the solvent more dispersible in tafluprost, polytrimethylene carbonate, chitosan and trilysine. In the present invention, the amount of the solvent to be used can be selected within a wide range.
In the present invention, the manner of dispersion and uniform mixing can be selected within a wide range. In some preferred embodiments, in order to make the prepared lacrimal punctum plug for slowly releasing tafluprost release tafluprost better and the slow release is more stable, ultrasonic dispersion is adopted, the ultrasonic dispersion time is 15-20min, and the ultrasonic power is 300-350W.
In the invention, the crosslinking reaction can be carried out at 40-50 ℃ for 8-20h, so as to obtain the lacrimal duct suppository which has good compliance of patients, good comfort, good biocompatibility, small side effect, short-term degradation and the like and can slowly release the tafluprost. In the present invention, the trilysine functions well as a crosslinking function. In some preferred embodiments, in step (2), the crosslinking reaction is carried out at 45 to 50 ℃. In some preferred embodiments, in step (2), the crosslinking reaction is carried out for 12 to 20 hours.
In the present invention, the conditions for cooling may be selected within a wide range, such as natural cooling to room temperature.
In the present invention, the drying conditions can be selected within a wide range, for example, drying at room temperature and atmospheric pressure for 0.5 to 3 hours.
In the present invention, the plasma treatment is performed under conditions of less than 6pa for 30s to 5 min. In some preferred embodiments, in order to make the prepared lacrimal punctum plug for slowly releasing tafluprost capable of further reducing the frequency of using antibiotic drugs or not, the compliance of patients is good, the punctum plug swells when meeting water, the comfort is good, the biocompatibility is good, the side effect is small, the short-term degradation is caused, in the step (3), the plasma treatment conditions comprise the treatment pressure of 3-5Pa, the treatment time of 30s-3min, the flow rate of Ar of 1-3L/min and the power of 50-90W.
In the invention, the inventor unexpectedly finds that the canalicular plug for slowly releasing the tafluprost can obtain very good hydrophilicity and water swelling property through plasma treatment after the tafluprost, the polytrimethylene carbonate, the chitosan and the trilysine are crosslinked to obtain a mixture, the puncticular plug can rapidly swell in water, and can rapidly swell in canalicular after being implanted within a few seconds, so that the puncticular plug is fixed in the canalicular and is not easy to fall off. The punctal plug can expand rapidly in the lacrimal canaliculus, such as within 6s, within 5s, or within 4s after implantation. When the punctum plug is cylindrical, the length or diameter of the punctum plug after implantation rapidly expands at least 3 times, at least 4 times, at least 5 times, or at least 6 times when exposed to water.
In some preferred embodiments, in step (1), the mass ratio of tafluprost to polytrimethylene carbonate to chitosan to trilysine is from 0.001 to 0.02: 25 to 35: 20 to 35: 0.5 to 1.
In the present invention, it is preferable that in order to further make the punctum plug which sustains tafluprost more comfortable when implanted into the lacrimal passage and less liable to come off, in step (3), when cured into a cylindrical shape, the diameter is 0.1 to 1mm and the length is 0.5 to 10mm. More preferably, in step (3), when cured to be shaped into a cylindrical shape, the diameter is 0.1 to 0.5mm and the length is 0.5 to 3mm.
In the present invention, preferably, in step (3), when the cured and molded cylindrical shape, at least one tear discharge hole is opened along the central axis, the position of the tear discharge hole can be centered on the central axis or around the central axis, and the diameter of the tear discharge hole is 0.02mm-0.2mm, which is beneficial to reducing tear loss and wetting the eyeball, and can also lead the tear to circulate and discharge through the through hole and reduce the accumulation and retention of the tear, so that the punctum plug slowly releasing tafluprost can timely discharge redundant tear, thereby reducing the related inflammation and the like caused by the accumulation and retention of the tear. The combination of the polytrimethylene carbonate and the chitosan which are used as main raw materials is not easy to produce inflammation, and the punctum suppository adopting the slow-release tafluprost has good anti-inflammatory effect. In the invention, the tear discharge holes can be punched after molding, and can also be obtained by a mold or 3D printing during preparation.
In the present invention, "short-term degradation" generally means degradation within 60 days, such as within 7 days, within 15 days, within 30 days, within 45 days.
In the present invention, "patient" is to be understood in a broad sense and includes animals such as mice, rabbits, dogs, cows, monkeys, etc., and humans.
In a second aspect, the present invention provides a punctum plug for sustained release of tafluprost, which is prepared according to the above preparation method.
The present invention will be described in detail below by way of examples and comparative examples. In the following examples and comparative examples, the drugs and agents are all conventionally commercially available.
Example 1: preparation example of lacrimal duct suppository for sustained release of tafluprost according to the present invention
A lacrimal canaliculus suppository for slowly releasing tafluprost is prepared by the following steps:
(1) Dispersing 0.001g of tafluprost, 25g of polytrimethylene carbonate (weight average molecular weight is 20000-50000), 35g of chitosan (weight average molecular weight is 50000-100000) and 0.6g of trilysine in 100ml of acetic acid aqueous solution (molar concentration is 5%), and then adopting ultrasonic dispersion for 15min, wherein the ultrasonic power is 300W, and uniformly mixing;
(2) Performing crosslinking reaction at 45 ℃, performing 12h, naturally cooling to room temperature, and drying for 2h at room temperature under normal pressure to obtain a mixture;
(3) And (3) carrying out plasma treatment on the mixture obtained in the step (2) at 4pa for 30s, wherein the flow rate of Ar is 1L/min, the power is 60W, then solidifying the mixture into a cylindrical shape with the diameter of 0.4mm and the length of 1mm, and opening a tear discharge hole with the diameter of 0.1mm to obtain the punctum plug P1 for slowly releasing tafluprost.
The punctum plug P1 for slowly releasing tafluprost prepared by the embodiment can be rapidly expanded 6.4 times in diameter within 4s and 5.9 times in length after meeting water, is good in comfort level, good in biocompatibility, small in side effect, not easy to fall off and degraded within 15 days.
Example 2: preparation example of lacrimal duct suppository for sustained release of tafluprost according to the present invention
A lacrimal canaliculus suppository for slowly releasing tafluprost is prepared by the following steps:
(1) Dispersing 0.004g of tafluprost, 35g of polytrimethylene carbonate (weight average molecular weight is 20000-50000), 25g of chitosan (weight average molecular weight is 50000-100000) and 1g of trilysine in 100ml of acetic acid aqueous solution (the molar concentration is 8%), then adopting ultrasonic dispersion for 20min, the ultrasonic power is 300W, and uniformly mixing;
(2) Performing crosslinking reaction at 50 ℃ for 12 hours, naturally cooling to room temperature, and drying at room temperature and normal pressure for 1.5 hours to obtain a mixture;
(3) And (3) carrying out plasma treatment on the mixture obtained in the step (2) at 3pa for 1min, wherein the flow rate of Ar is 2L/min, the power is 50W, then solidifying the mixture into a cylindrical shape with the diameter of 0.4mm and the length of 1mm, and opening a lacrimal drainage hole with the diameter of 0.1mm to obtain the punctum plug P2 for slowly releasing the tafluprost.
The punctum plug P2 for slowly releasing tafluprost prepared by the embodiment can be rapidly expanded 6.5 times in diameter within 5s and 5.7 times in length after meeting water, is good in comfort level, good in biocompatibility, small in side effect, not easy to fall off and degraded within 15 days.
Example 3: preparation example of lacrimal duct suppository for sustained release of tafluprost according to the present invention
A lacrimal canaliculus suppository for slowly releasing tafluprost is prepared by the following steps:
(1) Dispersing 0.002g of tafluprost, 30g of polytrimethylene carbonate (weight average molecular weight is 20000-50000), 20g of chitosan (weight average molecular weight is 50000-100000) and 0.8g of trilysine in 100ml of acetic acid aqueous solution (molar concentration is 3%), then adopting ultrasonic dispersion for 16min, the ultrasonic power is 350W, and uniformly mixing;
(2) Performing crosslinking reaction at 45 ℃, performing 15h, naturally cooling to room temperature, and drying for 2h at room temperature under normal pressure to obtain a mixture;
(3) And (3) carrying out plasma treatment on the mixture obtained in the step (2) at 5pa for 50s, wherein the flow rate of Ar is 1.5L/min, the power is 70W, then solidifying to obtain a cylindrical shape with the diameter of 0.5mm and the length of 0.8mm, and opening a lacrimal drainage hole with the diameter of 0.1mm to obtain the punctum plug P3 for slowly releasing tafluprost.
The punctum plug P3 of the slow-release tafluprost prepared by the embodiment can be rapidly expanded by 6.3 times in diameter within 5s and 5.5 times in length after meeting water, and is good in comfort level, good in biocompatibility, small in side effect, not easy to fall off and degraded within 15 days.
Example 4: preparation example of lacrimal duct suppository for sustained release of tafluprost according to the present invention
A lacrimal duct suppository for slowly releasing tafluprost is prepared by the following steps:
(1) Dispersing 0.006g of tafluprost, 32g of polytrimethylene carbonate (weight average molecular weight is 20000-50000), 28g of chitosan (weight average molecular weight is 50000-100000) and 0.7g of trilysine in 100ml of acetic acid aqueous solution (molar concentration is 5%), and then dispersing by adopting ultrasonic for 15min, wherein the ultrasonic power is 310W, and mixing uniformly;
(2) Performing crosslinking reaction at 50 ℃ for 12 hours, naturally cooling to room temperature, and drying at room temperature and normal pressure for 2.5 hours to obtain a mixture;
(3) And (3) carrying out plasma treatment on the mixture obtained in the step (2) at 3.5pa for 1min, wherein the flow rate of Ar is 2L/min, the power is 90W, then curing to obtain a cylindrical shape with the diameter of 0.4mm and the length of 1mm, opening a lacrimal drainage hole with the diameter of 0.1mm, and obtaining the punctum plug P4 for slowly releasing the tafluprost, wherein the punctum plug P4 is not easy to fall off.
The punctum plug P4 for slow release of tafluprost prepared by the embodiment can rapidly expand 5.9 times in diameter within 5 seconds and 5.2 times in length after meeting water, is good in comfort level, good in biocompatibility, small in side effect, not easy to fall off and degraded within 15 days.
Example 5: preparation example of lacrimal duct suppository for sustained release of tafluprost according to the present invention
A lacrimal canaliculus suppository for slowly releasing tafluprost is prepared by the following steps:
(1) Dispersing 0.008g of tafluprost, 31g of polytrimethylene carbonate (weight average molecular weight is 20000-50000), 29g of chitosan (weight average molecular weight is 50000-100000) and 0.6g of trilysine in 100ml of acetic acid aqueous solution (molar concentration is 5%), then adopting ultrasonic dispersion for 18min, and the ultrasonic power is 350W, and uniformly mixing;
(2) Performing crosslinking reaction at 48 ℃, performing 15h, naturally cooling to room temperature, and drying for 1h at room temperature under normal pressure to obtain a mixture;
(3) And (3) carrying out plasma treatment on the mixture obtained in the step (2) at 5pa for 1min, wherein the flow rate of Ar is 2.5L/min, the power is 80W, then solidifying to obtain a cylindrical shape with the diameter of 0.4mm and the length of 1.2mm, and opening a lacrimal drainage hole with the diameter of 0.1mm to obtain the punctum plug P5 for slowly releasing tafluprost.
The punctum plug P5 for slowly releasing tafluprost prepared by the embodiment can be rapidly expanded by 6.1 times in diameter within 6 seconds and 5.7 times in length after meeting water, is good in comfort level, good in biocompatibility, small in side effect, not easy to fall off and degraded within 15 days.
Example 6: preparation example of lacrimal duct suppository for sustained release of tafluprost according to the present invention
A lacrimal canaliculus suppository for slowly releasing tafluprost is prepared by the following steps:
(1) Dispersing 0.007g of tafluprost, 33g of polytrimethylene carbonate (with the weight-average molecular weight of 20000-50000), 27g of chitosan (with the weight-average molecular weight of 50000-100000) and 0.7g of trilysine in 100ml of acetic acid aqueous solution (with the molar concentration of 5%), then adopting ultrasonic dispersion for 15min, and the ultrasonic power of 340W, and uniformly mixing;
(2) Performing crosslinking reaction at 50 ℃, performing 15h, naturally cooling to room temperature, and drying for 2h at room temperature under normal pressure to obtain a mixture;
(3) And (3) carrying out plasma treatment 50s on the mixture obtained in the step (2) at 4pa, wherein the flow rate of Ar is 1.6L/min, the power is 90W, then solidifying to obtain a cylindrical shape with the diameter of 0.4mm and the length of 1mm, and opening a lacrimal drainage hole with the diameter of 0.1mm, thus obtaining the punctum plug P6 for slowly releasing the tafluprost.
The punctum plug P6 for slow release of tafluprost prepared by the embodiment can rapidly expand 5.8 times in diameter within 5 seconds and 5.5 times in length after meeting water, is good in comfort level, good in biocompatibility, small in side effect, not easy to fall off and degraded within 15 days.
Example 7: preparation example of lacrimal duct suppository for sustained release of tafluprost according to the present invention
A lacrimal canaliculus suppository for slowly releasing tafluprost is prepared by the following steps:
(1) Dispersing 0.005g of tafluprost, 31g of polytrimethylene carbonate (weight average molecular weight is 20000-50000), 29g of chitosan (weight average molecular weight is 50000-100000) and 1g of trilysine in 100ml of acetic acid aqueous solution (molar concentration is 5%), then adopting ultrasonic dispersion for 15min, wherein the ultrasonic power is 300W, and mixing uniformly;
(2) Performing crosslinking reaction at 45 ℃, performing 20h, naturally cooling to room temperature, and drying for 2h at room temperature under normal pressure to obtain a mixture;
(3) And (3) carrying out plasma treatment on the mixture obtained in the step (2) at 3pa for 2min, wherein the flow rate of Ar is 1L/min, the power is 60W, then curing to obtain a cylindrical shape with the diameter of 0.4mm and the length of 1.2mm, and opening a lacrimal drainage hole with the diameter of 0.1mm to obtain the punctum plug P7 for slowly releasing tafluprost.
The punctum plug P7 for slow release of tafluprost prepared by the embodiment can rapidly expand 6.6 times in diameter within 5 seconds and 5.9 times in length after meeting water, is good in comfort level, good in biocompatibility, small in side effect, not easy to fall off and degraded within 15 days.
Example 8: preparation example of lacrimal duct suppository for sustained release of tafluprost according to the present invention
A lacrimal duct suppository for slowly releasing tafluprost is prepared by the following steps:
(1) Dispersing 0.0016g of tafluprost, 37g of polytrimethylene carbonate (with the weight-average molecular weight of 20000-50000), 33g of chitosan (with the weight-average molecular weight of 50000-100000) and 0.9g of trilysine in 100ml of acetic acid aqueous solution (with the molar concentration of 5%), and then performing ultrasonic dispersion for 15min at the ultrasonic power of 350W, and uniformly mixing;
(2) Performing crosslinking reaction at 50 ℃, performing 15h, naturally cooling to room temperature, and drying for 1h at room temperature under normal pressure to obtain a mixture;
(3) And (3) carrying out plasma treatment on the mixture obtained in the step (2) at 3pa for 3min, wherein the flow rate of Ar is 1L/min, the power is 90W, then, curing to obtain a cylindrical shape with the diameter of 0.4mm and the length of 1mm, and opening a lacrimal drainage hole with the diameter of 0.1mm to obtain the punctum plug P8 for slowly releasing the tafluprost.
The punctum plug P8 for slowly releasing tafluprost prepared by the embodiment can be expanded by 6.2 times in diameter within 5s and 5.6 times in length after meeting water, is good in comfort level, good in biocompatibility, small in side effect, not easy to fall off and degraded within 15 days.
Comparative example 1: comparative example of inventive example 1
The starting material contained no polytrimethylene carbonate and the procedure was the same as in example 1 to obtain a punctum plug DPI that sustained release of tafluprost.
The punctum plug DP1 material of the slow release tafluprost prepared by the comparative example is too soft, is not beneficial to mechanical processing, is easy to fall off, and the release of tafluprost is unstable. Therefore, the polytrimethylene carbonate is added in the examples to obtain proper mechanical strength and good mechanical processing performance.
Comparative example 2: comparative example of inventive example 1
The other steps were the same as in example 1 without plasma treatment to obtain punctum plug DP2 that released tafluprost.
The punctum plug DP2 of the sustained release tafluprost prepared by the comparative example has slow water swelling speed, 4.2 times of diameter swelling in 10 hours and 3.6 times of length swelling.
Comparative example 3: comparative example of inventive example 1
The procedure of example 1 was followed without ultrasonic dispersion to obtain Tafluprost-sustained release punctum plug DP3.
The sustained release of the tafluprost-sustained release punctum plug DP3 prepared by the comparative example is not stable enough.
Example 9: the release experiment of the lacrimal duct suppository for slowly releasing the tafluprost
Simulated tear fluid was prepared according to the composition of human tear fluid, the punctal plugs prepared in examples 1 to 8 and comparative examples 1 to 3 were immersed in 5ml of the simulated tear fluid, respectively, and the concentration of tafluprost in the simulated tear fluid was measured, and the cumulative release rate of tafluprost was calculated based on the concentration of tafluprost. The cumulative release rate of tafluprost is shown in table 1.
TABLE 1 cumulative release rate of tafluprost
Figure BDA0003916313490000141
As can be seen from table 1 above, the punctal plugs for sustained release of tafluprost prepared in the above examples of the present invention can well promote slow release of tafluprost with a stable release rate, whereas the release of tafluprost of DP1 of comparative example 1 has been unstable, DP2 of comparative example 2 has a low rate of swelling with water, resulting in a small and unstable release of tafluprost within the first few hours, and thereafter tends to be stable, and the release of tafluprost of comparative example 3 has been unstable.
Example 10: the invention has the curative effect on xerophthalmia combined glaucoma
The evaluation criteria of the curative effect are as follows: the disappearance of symptoms was scored as 0, mild symptoms as 1, moderate symptoms as 2, and severe symptoms as 3. The effect is shown: the symptoms basically disappear, and the score is reduced by more than or equal to 80 percent; the method has the following advantages: symptoms are obviously improved, and 80 percent of score reduction is less than or equal to 30 percent; and (4) invalidation: no obvious improvement of symptoms. Total effective rate = (effective + effective)/total number of cases × 100%.
100 patients (18-59 years old) with dry eye and glaucoma were treated with the tafluprost-sustained release punctum plug P1 prepared in example 1 and the efficacy was evaluated on the 10 th day after the treatment, and the results are shown in Table 2.
The results show that: after the implantation of the slow release tafluprost for 10 days, the total effective rate of the lacrimal canaliculus suppository for slow release of tafluprost for dry eye syndrome combined glaucoma is 98%, the curative effect is obvious, and the slow release tafluprost has very obvious statistical significance.
Example 11: the invention has the curative effect on xerophthalmia and ocular hypertension
The evaluation criteria of the curative effect are as follows: the disappearance of symptoms was scored as 0, mild symptoms as 1, moderate symptoms as 2, and severe symptoms as 3. The effect is shown: the symptoms basically disappear, and the score is reduced by more than or equal to 80 percent; the method has the following advantages: symptoms are obviously improved, and 80 percent of score is reduced by less than or equal to 30 percent; and (4) invalidation: the symptoms are not obviously improved. Total effective rate = (effective + effective)/total number of cases × 100%.
100 patients (18-59 years old) with dry eye and ocular hypertension were implanted with the tafluprost-sustained release punctum plug P1 prepared in example 1, and the efficacy was evaluated on the 10 th day after implantation, and the results are shown in Table 2.
The results show that: after 10 days of implantation, the lacrimal canaliculus suppository for slowly releasing tafluprost has the total effective rate of 99 percent for xerophthalmia combined with ocular hypertension, has obvious curative effect and has very obvious statistical significance.
TABLE 2 evaluation results of therapeutic effects
Figure BDA0003916313490000161
The above ineffective cases are effective after P1 treatment is implanted again because the disease course of patients is longer and the treatment time is longer.
The prepared lacrimal duct suppository for slowly releasing the tafluprost has important clinical application value. It should be noted that the slow release lacrimal canaliculus of the tafluprost prepared by the invention can effectively treat xerophthalmia with glaucoma and xerophthalmia with ocular hypertension, but the xerophthalmia with glaucoma and xerophthalmia with ocular hypertension mentioned in the invention are only commonly used for treatment, but the invention is not limited to be applied to the ocular diseases, and the slow release lacrimal canaliculus of the tafluprost can be applied to any other suitable ocular diseases.
Finally, the above embodiments are only used to illustrate the technical solutions of the present invention, and do not limit the content of the present invention. Although the present invention has been described in considerable detail with reference to the embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (10)

1. A method for preparing a punctum plug for sustained release of tafluprost, comprising the steps of:
(1) Dispersing tafluprost, polytrimethylene carbonate, chitosan and trilysine in a solvent and uniformly mixing, wherein the mass ratio of the tafluprost to the polytrimethylene carbonate to the chitosan to the trilysine is 0.001-0.5: 15-35: 10-35: 0.5-2;
(2) Performing crosslinking reaction at 40-50 deg.C for 8-20h, cooling, and drying to obtain mixture;
(3) And (3) carrying out plasma treatment on the mixture obtained in the step (2) for 30s-5min under the condition of less than 6pa, and then curing and forming to obtain the canaliculus plug for slowly releasing tafluprost.
2. The method for preparing a punctum plug for the sustained release of tafluprost according to claim 1, wherein the mass ratio of tafluprost to polytrimethylene carbonate to chitosan to trilysine in step (1) is 0.001-0.02: 25-35: 20-35: 0.5-1.
3. The method for preparing a punctum plug for the sustained release of tafluprost according to claim 1, wherein the solvent is acetic acid in step (1).
4. The method for preparing a punctal plug that sustains tafluprost according to claim 1, wherein in step (2), the crosslinking reaction is carried out at 45 to 50 ℃.
5. The method for preparing a punctal plug that sustains tafluprost according to claim 1, wherein the crosslinking reaction is performed for 12 to 20 hours in step (2).
6. The method for preparing a punctum plug for the sustained release of tafluprost according to claim 1, wherein in step (3), the plasma treatment conditions include a treatment pressure of 3 to 5Pa, a treatment time of 30s to 3min, a flow rate of Ar of 1 to 3L/min, and a power of 50 to 90W.
7. The method for preparing a punctal plug that sustains release of tafluprost according to claim 1, wherein in step (3), when cured into a cylindrical shape, the diameter is 0.1 to 1mm and the length is 0.5 to 10mm.
8. The method for preparing a punctal plug that sustains tafluprost according to claim 7, wherein in step (3), when cured into a cylindrical shape, the diameter is 0.1 to 0.5mm and the length is 0.5 to 3mm.
9. The method for preparing a punctum plug that sustains tafluprost according to claim 7, wherein in step (3), at least one row of lacrimal pores, which have a diameter of 0.02mm to 0.2mm, is opened in the direction of the central axis when cured into a cylindrical shape.
10. A punctal plug for sustained release of tafluprost, characterized in that it is prepared according to the preparation method of any one of claims 1 to 9.
CN202211342754.6A 2022-10-30 2022-10-30 Lacrimal duct suppository for slowly releasing tafluprost and preparation method thereof Pending CN115531289A (en)

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